1. Field of the Invention
The present invention relates to a novel protein and a gene thereof which is involved in bone metabolism. Further, the present invention relates to a novel protein and the gene thereof having a function or an activity of (i) promoting differentiation of osteoblast, (ii) inducing morphological change of a cell or (iii) an esterase activity, etc.
2. Prior Art
Normal bone metabolism depends on a balance between bone formation and born resorption. It has been known that bone formation is mainly led by osteoblast that is differentiated from a messenchymal stem cell and bone resorption is led by osteoclast that is differentiated from a hematopoietic stem cell.
It is thought that osteoporosis is caused when this balance is shifted to the bone resorption side. Osteoporosis is classified into two types. One is called postmenoposal osteoporosis in which remarkable decrease in bone mass is observed. In this type, bone metabolism is at a high turnover rate, and bone formation and bone resorption are both active. However, the balance is shifted toward the bone resorption side, thereby causing osteoporosis. The other type is called a senile osteoporosis in which a decrease in bone mass is caused gradually. In this type, a cause is thought to be a dysfunction of the osteoblast, which leads to a declined balance toward the bone resorption side.
There have been many points that are left unclear about mechanisms of the bone formation or of differentiation of osteoblasts, for example, as a factor that is involved in differentiation of osteoblasts, only a few have been known, such as bone morphogenetic protein (BMP) (Maiti, et al., Indian J. Exp. Biol., vol. 36, pp. 237 to 244, 1998), a transcription factor Cbfal (Komori, et al., Cell, vol. 89, pp. 755 to 764, 1997), etc.
On bone remodeling, there have been known facts as follows. That is, when a concentration of calcium ion in blood is lowered, secretion of parathyroid hormone (PTH) from accessory thyroid gland is increased, and PTH directly acts on bone, causing bone resorption and calcium ion release. In this process, it is known that PTH acts on osteoblasts and induces morphological change of the cells. There is a hypothesis advocating that a part of a bone surface covered by osteoblasts is exposed due to such morphological change of the osteoblasts, thereby providing a space for osteoclasts to adhere to (Rodan et al., Calcit. Tissue Int., vol. 33, pp. 349 to 351, 1981; “Principles of Bone Biology” (J. P. Bilezikian, L. G. Raisz, G. A. Rodan, eds.), 1996, Academic Press Inc., USA.). At an initial stage of bone resorption of bone remodeling, adhesion of osteoclasts to the bone surface is of importance, and, morphological change of osteoblasts is also as important. Despite of this, there has not been known much about a detailed mechanism of morphological change of osteoblasts during bone remodeling.
It has been earnestly desired that these mechanisms are solved for research and development of a therapeutic treatment method and a therapeutic agent for diseases related to bone metabolism, such as osteoporosis, etc.